Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function.

Abstract	The human tripartite motif (TRIM) family comprises 70 members, including HIV restriction factor TRIM5alpha and disease-associated proteins TRIM20 (pyrin) and TRIM21. TRIM proteins have conserved domain architecture but diverse cellular roles. Here, we describe how the C-terminal PRYSPRY domain mediates diverse TRIM functions. The crystal structure of TRIM21 PRYSPRY in complex with its target IgG Fc reveals a canonical binding interface comprised of two discrete pockets formed by antibody-like variable loops. Alanine scanning of this interface has identified the hot-spot residues that control TRIM21 binding to Fc; the same hot-spots control HIV/murine leukemia virus restriction by TRIM5alpha and mediate severe familial Mediterranean fever in TRIM20/pyrin. Characterization of the IgG binding site for TRIM21 PRYSPRY reveals TRIM21 as a superantigen analogous to bacterial protein A and suggests that an antibody bipolar bridging mechanism may contribute to the pathogenic accumulation of anti-TRIM21 autoantibody immune complex in autoimmune disease.
Authors	Leo C James, Anthony H Keeble, Zahra Khan, David A Rhodes, John Trowsdale
Journal	Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 104 Issue 15 Pg. 6200-5 (Apr 10 2007) ISSN: 0027-8424 [Print] United States
PMID	17400754 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Autoantibodies DNA-Binding Proteins Immunoglobulin G Nuclear Proteins Ribonucleoproteins SS-A antigen
Topics	Amino Acid Sequence Autoantibodies (genetics) Autoimmune Diseases (genetics, immunology) Binding Sites, Antibody (genetics) Calorimetry Cell Line Crystallography DNA-Binding Proteins (chemistry) Fluorescence Polarization Gene Expression Humans Immunoglobulin G (chemistry) Models, Molecular Molecular Sequence Data Multigene Family (genetics) Nuclear Proteins (chemistry) Protein Binding Protein Conformation Protein Structure, Tertiary Ribonucleoproteins Sequence Alignment Structure-Activity Relationship

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